A Phase I/II Study of the Efficacy and Toxicity of Humanized Anti-Tac (Zenapax(Trademark)) in the Therapy of Tac-Expressing Adult T-Cell Leukemia

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Bethesda,
Maryland20892

Purpose:

The purpose of the study is to determine: (1) the toxicity and maximum tolerated dose (MTD)
of humanized anti-Tac (daclizumab), (Zenapax(Registered Trademark)) in patients with ATL;
(2) to define the dose of Zenapax(Registered Trademark) required to saturate IL-2R alpha in
patients with ATL; (3) determine the clinical response to humanized (Hu) anti-Tac
(Zenapax(Registered Trademark) of patients with Tac-expressing adult T-cell leukemia; and
(4) determine the serum dieaway curve (pharmacokinetics) of infused humanized (Hu)-anti-Tac
in patients who have ATL. This study represents an extension of Metabolism Branch NCI
protocols utilizing modifications of the original murine anti-Tac monoclonal antibody (mAb)
developed by our group for the treatment of ATL. The scientific basis for these therapeutic
studies is that the leukemic cells of patients with ATL express abnormally high levels of
the Tac antigen (IL-2R alpha) on their surface whereas resting normal cells including normal
T-cells of the patients do not. One presumed mode of action of Hu-anti-Tac in the treatment
of ATL involves the interruption of the interaction of IL-2 with its growth factor receptor.
To be effective in this goal we must maintain saturation of the IL-2 receptors (IL-2R) with
humanized anti-Tac thereby preventing IL-2 mediated proliferation and yielding cytokine
deprivation and apoptotic cell death of the leukemic cells. Eligible patients with ATL
will be treated with escalating doses of Zenapax(Registered Trademark) between groups in the
Clinical Center of the NIH. Groups of patients will receive sufficient Zenapax(Registered
Trademark) to yield saturation of the IL-2 receptor for a period of 17 weeks. Following an
initial loading dose, the responding patients will receive subsequent doses at week 2 and
then at 3 week intervals for a total of 6 doses. Clinical response will be evaluated using
routine immunological and clinical evaluation and by monitoring the saturation of the IL-2R
and the absolute number of residual circulating malignant cells by FACS analysis using two
fluorochrome-labeled non-crossreacting antibodies to the IL-2 receptor, anti-Tac and 7G7/B6,
as well as antibodies to CD3, CD4, CD7, and CD8. Furthermore, responses will be evaluated
in patients with leukemia by Southern blot analysis of the arrangement of the T-cell
receptor genes and HTLV-I integration. Finally, in select patients, to define the
pharmacokinetics of the therapeutic antibody, we plan to monitor the serum levels of the
infused Hu-anti-Tac (Zenapax(Registered Trademark)) as a function of time. This study is an
essential element of our program involving IL-2R-directed therapeutic studies. If as
anticipated the therapy with humanized anti-Tac yields some partial and complete remissions
in patients with ATL, we will propose that it be used as a single agent for patients with
smoldering and chronic ATL and in association with chemotherapeutic agents to provide a
novel approach for the treatment of acute and lymphoma forms of ATL. In a subsequent
addition to this protocol, we will propose that patients not manifesting a remission with
Zenapax(Registered Trademark) alone will cross over to a therapeutic regimen that includes
saturating doses of Zenapax(Registered Trademark) as well as additional agents directed
toward ATL (e.g., zidovudine (AZT)/IFN). We also plan a future clinical trial where we will
evaluate the efficacy and toxicity in ATL patients of saturating doses of Zenapax(Registered
Trademark) as compared to identical doses of Zenapax(Registered Trademark) given in
association with (90)Y-armed 7G7/B6, a non-competing antibody to IL-2R alpha or in
combination with chemotherapy.

Study summary:

Background:
HTLV-1-associated adult T cell leukemia/lymphoma (ATL) is an aggressive lymphoproliferative
disorder.
Chemotherapy has had limited impact on survival.
The IL-2R alpha (CD25) is over expressed on ATL cells and the smoldering and chronic stages
of ATL are often IL-2 dependent.
The monoclonal antibody daclizumab (Zenapax) inhibits IL-2 binding to its receptor.
It is hypothesized that daclizumab may inhibit ATL growth.
Objectives:
To determine the toxicity and maximum tolerated dose (MTD) of humanized anti-Tac
(daclizumab, Zenapax) in patients with ATL.
To define the dose of Zenapax required to saturate IL-2R alpha in patients with ATL.
To determine the clinical response to humanized (Hu) anti-Tac (Zenapax) of patients with
Tac-expressing smoldering and chronic stage adult T cell leukemia.
To determine the serum dieaway curve (pharmacokinetics) of infused humanized (Hu) - anti -
Tac in patients who have ATL.
Eligibility:
Smoldering and chronic stage HTLV-1-associated adult T cell leukemia.
At least 5 percent of malignant cells in the peripheral blood or lymph nodes must react with
the anti-Tac (CD25) antibody.
Age greater than or equal to 10-years-old.
Patients must have measurable disease.
Patients with and without prior treatment.
Patients must have a granulocyte count of greater than or equal to 500/micro L, platelets
greater than or equal to 25,000/micro L, and creatinine less than 3.0 gm/dL.
Design:
Patients with smoldering or chronic stage ATL will be treated with intravenous daclizumab 8
mg/kg on day 0 and weeks 2, 5, 8, 11 and 14. Patients achieving a response will continue on
treatment with daclizumab 8 mg/kg every 3 weeks for up to 24 months. Patients achieving a
complete response (CR) will continue on treatment with daclizumab 8mg/kg every 3 weeks for
up to 24 months. Patients achieving a partial response (PR) will be maintained on
daclizumab 8 mg/kg administered every 3 weeks provided the PR is maintained and no serious
adverse event or toxicity related to daclizumab therapy is observed.

Criteria:

- ELIGIBILITY CRITERIA:
Population Base.
Patients diagnosed with smoldering or chronic HTLV-I- associated adult T-cell leukemia.
INCLUSION CRITERIA:
Patients must have serum antibodies directed to HTLV-I.
All patients must have a histologically confirmed diagnosis of adult T-cell
leukemia/lymphoma.
At least 5 percent of each patient's peripheral blood, lymph node, pulmonary or dermal
malignant cells must react with the anti-Tac mAb as determined by immunofluorescent
staining or, alternatively, the serum-soluble IL-2 receptor levels must be greater than
1,000 units/ml (normal geometric mean, 235; with a 95% confidence interval of 112 to 502
units/mL).
Smoldering or chronic stage Tac-expressing adult T-cell leukemia defined by the Shimomyama
Criteria (37) are eligible. To be diagnosed as smoldering ATL, the patient must have a
normal lymphocyte count (less than 4 times 10(3)/mm(3)), less than or equal to 5 percent
abnormal lymphocytes on morphologic examination of the peripheral blood smear or on FACS
analysis (cells with a homogenous staining pattern and a greater than 1 log increase in
the magnitude of fluorescence emission of the anti-Tac peak over background expression),
no hypercalcemia, lactate dehydrogenase less than or equal to 1.5 times the upper limit of
normal, no lymphadenopathy, no involvement of extra nodal organs except skin or lung and
no malignant pleural effusion or ascites. If the abnormal lymphocyte count is less than
5percent, the patient must have at least one histologically proven skin ATL lesion to be
diagnosed as smoldering ATL.
Patients must have measurable disease. All patients with greater than 5 percent abnormal
(i.e., Tac homogenous strongly expressing) PBMC in the peripheral blood will be deemed to
have measurable disease.
The patient must have a granulocyte count of at least 500/mm(3) and a platelet count of
25,000/mm(3).
Patients must have a creatinine of less than 3.0 mg/dl.
Patients must have a Karnofsky performance score of greater than 60 percent.
ATL patients without, as well as those with, previous chemotherapy will be eligible for
inclusion in the study.
Patients with previous therapy with a monoclonal antibody including anti-Tac will be
eligible for the study provided that they do not have a positive HAHA (human antibody to
humanized anti-Tac) value (i.e., such patients must have a value greater than 250 ng/ml).
Omission of cytotoxic chemotherapy for ATL for 3 weeks prior to entry into the trial is
required. However, patients receiving corticosteroids will not be excluded.
Patients must have a life expectancy of greater than 2 months.
Eligible patients must be greater than or equal to 10 years old. There is no upper age
limit..
Patients over the age of 18 years must be able to understand and sign an Informed Consent
form. Eligible minors greater than or equal to 10 years old must give assent to
participate in this study.
EXCLUSION CRITERIA:
Patients with symptomatic central nervous system disease that is due to the adult T-cell
leukemia will be excluded. However, patients that have both ATL and another
HTLV-I-associated disease, tropical spastic paraparesis (TSP), will be included.
Furthermore, Tac-expressing T cells may be present in the CSF as long as the patient does
not have symptomatic CNS disease.
Pregnant and/or nursing patients are not eligible for the study.
HIV positive patients are excluded from the study.
Patients with SGOT or SGPT values 5.0-fold greater than the upper limit of normal or
bilirubin greater than 2.9 mg/dl will be excluded. If a liver function test is judged to
be elevated due to the underlying ATL, this parameter will be considered an unevaluable
parameter for toxicity determinations.
Acute or Lymphoma stage HTLV-1 associated adult T cell leukemia.

NCT ID:

NCT00001941

Primary Contact:

N/A

Backup Contact:

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Location Contact:

Bethesda, Maryland 20892United States

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Site Status: N/A

Data Source: ClinicalTrials.gov

Date Processed: June 25, 2018

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